Abstract 292: Notch Inhibition Stabilizes the Progression of Small Abdominal Aortic Aneurysm in a Mouse Model

Abstract

The progression of abdominal aortic aneurysm (AAA) involves a sustained influx of proinflammatory macrophages, which exacerbate tissue injury by releasing cytokines, chemokines and matrix metalloproteinases (MMPs). While multiple factors are involved in disease pathogenesis, the critical stimulus is the differentiation and infiltration of naïve macrophages (Mϕ) towards classical (M1) activation. In contrast, Mϕ can also be programmed to M2-macrophages which inhibit the inflammatory response and promote tissue repair. Previously, we showed that Notch deficiency reduces the development of AAA in the angiotensin II (AngII)-induced mouse model by preventing infiltration of Mϕ. Because of its regulatory roles in macrophage differentiation, we examined if Notch inhibition in a mouse model prevents progression of small AAA and if these effects are associated with Mϕ-differentiation. Notch inhibition (DAPT) started at day 3 or 8 of AngII infusion arrested the progression of AAA in Apoe -/- mice as demonstrated by a decreased luminal diameter and aortic width. The abdominal aortae treated with DAPT showed decreased MMPs expression and presence of elastin precursors including tropoelastin. Marginal adventitial thickening observed in DAPT-treated Apoe -/- mice was not associated with increased total macrophage content. Instead, DAPT-treated abdominal aortae showed increased expression of Cd206 positive M2-macrophages and decreased expression of Il12 positive M1-macrophages. Increased expression of IL12 positive M1 macrophages and its strong correlation with active Notch1 signaling (NICD) was also observed in the infrarenal aortae from AAA patients. Notch1 deficiency promoted M2-differentiation of Mϕ by upregulating transforming growth factor ( Tgf)-β2 expression in bone marrow-derived Mϕ at basal levels and in response to IL4. Protein expression of Tgf-β2 and its downstream pSmad2 also increased in DAPT-treated Apoe -/- mice, indicating a potential link between Notch and Tgf-β2 signaling in the M2-differentiation of Mϕ. Overall, Notch inhibition stabilizes the progression of AAA by macrophage-differentiation-dependent mechanisms and provides insights for novel therapeutic strategies to prevent the progression of small AAA.